Director's Report to the National Advisory Council on Drug Abuse - February, 2006

Research Findings - Basic Behavioral Research

The Ventral Pallidum Has Multiple Roles In Encoding Reward Cues And Generating Responses To Natural Rewards

The ventral pallidum (VP), an output nucleus of the striatum, is a focal point for brain limbic circuits, receiving projections from, among other areas, the nucleus accumbens (NAS) and ventral tegmental dopamine neurons. VP is known to be an important substrate for natural and drug reward. Two studies from the laboratories of Kent Berridge and J. Wayne Aldridge have now further elucidated the function of VP neurons. One study asked how the VP contributes to the generation of hedonic impact of a natural reward and the motivation to eat. Using a novel microinjection and functional mapping procedure, the investigators neuroanatomically localized and neurochemically characterized substrates in the VP that mediate increases in eating behavior and enhancements in taste hedonic "liking" reactions, which are assessed in the rat by taste reactivity measures such as licking and orofacial reactions to droplets of sucrose. They tested the effects of locally altering _-opioid and GABAA transmission, because signals from NAS to VP are carried by these transmitters. Although opioids are generally associated with increased hedonic response and eating behavior, they found that the _-opioid agonist DAMGO caused increased "liking" reactions to sucrose only in the posterior VP and actually suppressed such reactions in the anterior and central VP. DAMGO similarly stimulated eating behavior in the posterior and central VP and suppressed eating in the anterior VP. In contrast, the GABAA antagonist bicuculline increased eating behavior at all VP sites, yet completely failed to enhance sucrose "liking" reactions at any site. These results reveal that the VP has dissociable functions in generating increased food reward and increased eating behavior, and also that hedonic enhancement and eating are systematically mapped within the VP. The second study used neurophysiological approaches to examine how reward is coded by VP neurons, and test the effects of amphetamine on this encoding. Rats learned that a Pavlovian conditioned stimulus (CS+1 tone) predicted a second conditioned stimulus (CS+2 feeder click) followed by an unconditioned stimulus (UCS sucrose reward). Some rats were sensitized to amphetamine after training. Electrophysiological activity of ventral pallidal neurons was later recorded under the influence of vehicle or acute amphetamine injection. Both sensitization and acute amphetamine increased VP firing at CS+2, but produced no changes at CS+1 and minimal changes to UCS. The investigators used a new computational approach called 'Profile Analysis' to gain more insight into the behavioral relevance of these alterations in firing patterns. The analysis showed that mesolimbic activation by prior sensitization or acute amphetamine incrementally shifted neuronal firing profiles away from prediction signal coding (maximal at CS+1) and toward incentive coding (maximal at CS+2), without changing hedonic impact coding (maximal at UCS). This pattern suggests that mesolimbic activation produces a transformation from predictive information into incentive salience coded in VP neuron firing patterns. These results support predictions from incentive-sensitization theories and suggest why cues temporally proximal to drug presentation may precipitate cue-triggered relapse in human addicts. Smith, K.S. and Berridge, K.C. The Ventral Pallidum and Hedonic Reward: Neurochemical Maps of Sucrose "Liking" and Food Intake. The Journal of Neuroscience, 25, pp. 8637- 8649, 2005. Tindell, A.J., Berridge, K.C., Zhang, J., Peci–a, S. and Aldridge, J.W. Ventral Pallidal Neurons Code Incentive Motivation: Amplification by Mesolimbic Sensitization and Amphetamine. European Journal of Neuroscience, 22, pp. 2617-2634, 2005.

The Orexin System May Be a Therapeutic Target for Treatment of Drug Addiction

The orexins (or hypocretins) are neuropeptides recently identified as neurotransmitters in lateral hypothalamic neurons. While the lateral hypothalamus has been historically implicated in reward and motivation, it has mostly been studied with respect to feeding behavior. Although orexins have been proposed to have a function in feeding, most studies have focused on their role in arousal and sleep. Anatomical studies, however, show that orexin neurons in the lateral hypothalamus project to reward-associated brain regions, including the nucleus accumbens and ventral tegmental area. This pattern of projections suggested to the investigators that orexin neurons may have a general role in reward and motivation, consistent with their proposed function in feeding. The study combined the use of a conditioned place-preference procedure to measure the rewarding properties of morphine, cocaine and food with immunohistochemical techniques to determine whether orexin neurons were activated when rats expressed a preference for environments associated with the rewards. The investigators found that activation of lateral hypothalamic orexin neurons is strongly linked to preferences for cues associated with both drug and food reward. They then tested the functional implications of this activation by chemically activating lateral hypothalamic orexin neurons. This activation reinstated drug-seeking behavior. They obtained further evidence for a direct role of orexin in reinstatement by showing that reinstatement was completely blocked by prior administration of an orexin A antagonist. Further, they discovered that administration of the orexin A peptide directly into the ventral tegmental area would reinstate drug seeking. These data reveal a new role for lateral hypothalamus orexin neurons in reward seeking, drug relapse, and addiction, and implicate these neurons in the circuitry that integrates environmental cues with consummatory rewards. These findings may have significant implications for development of treatments for drug addiction, because they extend the therapeutic potential for the orexin system, which has been studied intensively as a target for treatment of sleep and eating disorders. Harris, G.C., Wimmer, M. and Aston-Jones, G. A Role for Lateral Hypothalamic Orexin Neurons in Reward Seeking. Nature, 437, pp. 556-559, 2005.

New Behavioral Apparatus for Concurrent Measures of Feeding and Locomotion In Rats

Drug abuse researchers are increasingly interested in monitoring more than one behavior simultaneously, and in behavioral assessment conducted in more naturalistic settings. However, problems arise when one activity can interfere with another. For example, psychostimulants induce locomotion and stereotypy, and also suppress eating. Studies of the biobehavioral actions of psychostimulants commonly focus on locomotion and less commonly on feeding, and only rarely are these measures used concurrently in the same animal. Since hyperactivity induced by a psychostimulant may compete with other motor behaviors, including eating, it would be useful to concurrently assess changes in eating and locomotion after psychostimulant treatment. To address this need, Dr. Paul Wellman and his colleagues modified an automated activity chamber in order to obtain minute-by-minute recordings of food consumption in parallel with an assessment of locomotion. In this apparatus, rats are offered a palatable mash diet suspended from an electronic balance positioned on the ceiling of the activity chamber. (The use of a palatable diet ensures that the rats will eat an adequate and consistent amount during a one hour test session, without the need for food deprivation). As a test of this system, they performed an experiment to characterize temporal changes in both locomotion and eating produced by administration of hypophagic doses of nicotine tartrate (0.28 mg/kg, i.p.) or cocaine hydrochloride (7.5 mg/kg, i.p.). At these doses, nicotine suppressed eating and locomotion, whereas cocaine suppressed eating, but facilitated forward locomotion. These outcomes support the viability of the apparatus and the concurrent method for dissociating drug effects on both feeding and locomotion. Dr. Wellman will be using this apparatus in his studies on the behavioral functions of _-1 adrenoreceptor subtypes with the goal of identifying new drugs that inhibit eating without activating brain reinforcement systems. Wellman, P.J., Ho, D.H. and Davis, K.W. Concurrent Measures of Feeding and Locomotion in Rats. Physiology & Behavior, 84, pp. 769-774, 2005.

CART peptides were originally identified because their cDNA was up-regulated in the striatum, but not elsewhere in the brain, by acute cocaine and amphetamine administration. This finding led Dr. Pastor Couceyro and his colleagues to suspect that CART peptides might be important for the behavioral actions and addictive properties of psychostimulants. In their studies, the behavioral effects of cocaine and amphetamine were examined in CART knockout (KO) and wild-type (WT) mice. They found that acute amphetamine administration increased ambulatory locomotor activity in both WT and CART KO animals, but whereas the WT mice also exhibited greater vertical activity, stereotyped grooming, and head bobbing at the higher doses, the CART KO mice did not. Repeated amphetamine treatment produced robust locomotor sensitization in WT mice but only rarely did so in CART KO mice. Amphetamine elicited conditioned place preference in both genotypes, but its potency was reduced in the CART KO mice such that only the highest dose produced conditioning equal to that observed in the WT mice. Intravenous cocaine self-administration was also observed in both genotypes, but CART KO mice consumed less cocaine and responded less than did WT mice. Although the behavioral effects of psychostimulants were generally reduced in the CART KO mice relative to WT, open field activity and sucrose preference were not significantly different between the two groups. The attenuated effects of amphetamine and cocaine in CART KO mice suggest a positive neuromodulatory role for CART peptides in the locomotor and motivational properties of psychostimulants and implicate CART peptides in psychostimulant addiction. Couceyro, P.R., Evans, C., McKinzie, A., Mitchell, D., Dube, M., Hagshenas, L., White, F.J., Douglass, J., Richards, W.G., and Bannon, A.W. Cocaine- and amphetamine-regulated transcript (CART) Peptides Modulate the Locomotor and Motivational Properties of Psychostimulants. The Journal of Pharmacology and Experimental Therapeutics, 315, pp. 1091-1100, 2005.

Cocaine Exposure Makes Actions Insensitive To Outcomes But Not To Extinction

This study investigated the behavioral processes that are involved in persistent drug seeking despite adverse outcomes, which characterizes drug addiction. Such behavior might be explained by drug-induced modifications in learning circuits, causing drug-seeking to become so habitual that it is impervious to outcome. Another possibility is that drug exposure reduces response inhibition. A third hypothesis, favored by Drs. Schoenbaum and Setlow from the results of this study, is that addictive behavior results from drug-induced alterations in the orbitofrontal cortex (OFC) resulting in decreased control of behavior by the value of expected outcomes. To test whether drug exposure can cause persistent behavior, and to distinguish between these accounts of such behavior, the investigators tested rats that had been exposed to 14 days of cocaine injections (and saline injected control animals) in a Pavlovian 'reinforcer devaluation' task, which provides independent assessments of the control of behavior by antecedent cues versus outcome representations. Twenty-one days after the cocaine (or saline control) treatment, rats were trained in the devaluation task: light cues (CS) were paired with food (UCS) for eight daily sessions and conditioning was assessed by response to the CS. After this conditioning, rats were assigned to either the 'devalued' or 'non-devalued' groups. The 'devalued' group received taste aversion training on days 1 and 3 by administration of LiCl immediately after free access to the same food used as the UCS. The 'non-devalued' group also received LiCl on days 1 and 3, but they received food pellets only on days 2 and 4. After training, probe tests consisted of presentation of the light CS in the absence of food delivery, and other tests were conducted to evaluate the conditioned taste aversion. The main result was that, during the probe tests, saline-treated devalued rats spent significantly less time in the food cups in response to the light CS compared to their non-devalued counterparts, whereas for cocaine-treated rats, there was no difference in responding between the devalued and non-devalued groups. Cocaine-treated animals did show extinction at the same rate as saline-treated animals during repeated exposure to CS alone, although their responses remained higher because they were elevated on the first day of extinction training. Thus, cocaine exposure caused persistent responding a month after the last drug treatment, and this deficit resulted from an inability to use representations of outcome value to guide behavior rather than from changes in stimulus-response learning or response inhibition. The results suggest that alterations in OFC, which is known to be involved in devaluation learning, may be extremely important for persistent drug-seeking behavior in the face of adverse outcomes. Schoenbaum, G. and Setlow, B. Cocaine Makes Actions Insensitive to Outcomes but not Extinction: Implications for Altered Orbitofrontal-Amygdalar Function. Cerebral Cortex, 15, pp. 1162-1169, 2005.

Studies comparing cocaine self-administration in male and female rats have found that females exhibit greater sensitivity in a variety of outcomes; for example, they acquire self-administration more quickly, a greater percentage of females acquire self-administration, females exhibit greater disruption in the diurnal control over cocaine intake, and they exhibit greater motivation for cocaine. Additionally, females exhibit greater cocaine-primed reinstatement of cocaine-seeking behavior. Dr. Ron See and colleagues at the Medical University of South Carolina now report sex differences in reinstatement of cocaine seeking behavior using a conditioned-cue procedure. Separate groups of rats were trained to bar press for varying doses of i.v. cocaine (0.25, 0.4, 0.5, 0.6, and 1.0 mg/kg per infusion). Each infusion was paired with a compound conditioned stimulus (CS) consisting of a light and tone. Following the establishment of stable cocaine self-administration, cocaine responding was extinguished and during reinstatement, the ability of the CS alone (without cocaine) was assessed. During the extinction period, females exhibited more extinction responses (i.e., greater resistance to extinction) than males, perhaps reflecting greater cocaine motivation. During the reinstatement period in which bar-presses produced the CS, but not cocaine, both males and females in all the training dose groups exhibited increased bar-pressing relative to the extinction responding. At intermediate training doses (0.4, 0.5, 0.6 mg/kg) there were no sex differences in reinstatement. Females trained at the lowest dose (0.25 mg/kg) and the highest dose (1.0mg/kg), however, exhibited less bar pressing for the CS than did males. Analysis of reinstatement by females tested during the estrous phase (versus non-estrous) indicated that those trained on the 0.25 mg/kg dose did not show reinstatement, although estrous status did not affect reinstatement at the other training doses. In summary, sex differences in reinstatement occurred at the highest and lowest training dose wherein reinstatement was greater in males than females and at the lowest training dose reinstatement was not observed in estrous females. Given that prior research has shown greater cocaine-primed reinstatement in females than males, the authors suggest that there are sex differences in the variables that control reinstatement. Specifically, females may be more vulnerable to pharmacologically induced reinstatement, whereas males may be more vulnerable to conditioned cue-induced reinstatement. Further research on these sex differences, including hormonal control, and their implications for relapse in humans is warranted. Fuchs, R.A., Evans, A., Mehta, R.H., Case, J. M. and See, R.E. Influence of Sex and Estrous Cyclicity on Conditioned Cue-induced Reinstatement of Cocaine-seeking Behavior in Rats. Psychopharmacology, 179, pp. 662-672, 2005.

Exogenous Progesterone Attenuates the Subjective Effects of Smoked Cocaine In Women, But Not In Men

Several preclinical studies have shown greater sensitivity to cocaine in females as compared to males. Further, many of these behavioral effects are modulated by the estrous cycle, and are eliminated by ovariectomy and subsequently restored by administration of estradiol, suggesting a role for estradiol in male-female differences in cocaine sensitivity. On the other hand, there is suggestive evidence from both preclinical and clinical studies that progesterone may also play a role in cocaine's subjective effects and may contribute to male-female differences in cocaine sensitivity. Drs. Suzette Evans and Richard Foltin of the New York State Psychiatric Institute and Columbia University pursued this possibility by comparing the subjective effects of exogenously administered progesterone in males and in females. In inpatient sessions, each female was studied in the mid-luteal phase (when both progesterone and estradiol were elevated), in the follicular phase (when progesterone was negligible and estradiol was elevated), and in a follicular phase in which progesterone was administered. A dose of 150 mg oral micronized progesterone was given so that the progesterone levels approximated those of the mid-luteal phase. Each male was studied under progesterone administration and under placebo. For each subject a full cocaine dose-response curve (0, 6, 12, and 25 mg cocaine) was obtained in each session. Replicating prior studies, cocaine's subjective effects were greater in the follicular phase than the luteal. Progesterone administration during the follicular phase resulted in an attenuation of the positive subjective effects, but did not alter the subjective effects in males. Drs. Evans and Foltin are now conducting a study to determine whether the administration of progesterone will attenuate cocaine self-administration. Evans, S.M. and Foltin, R.W. Exogenous Progesterone Attenuates the Subjective Effects of Smoked Cocaine in Women, But Not in Men. Neuropsychopharmacology (Online publication: 4 August 2005 at http://www.acnp.org/citations/Npp080405050186/default.pdf )

This study investigated the acute effects of smoking a low- or high-nicotine cigarette on HPA hormones, subjective effects and cardiovascular measures in healthy, nicotine-dependent men. The high-nicotine cigarette was associated with higher peak plasma nicotine levels, and higher ratings on "high", "rush", "liking", and reduced ratings of "craving". Plasma ACTH levels and epinephrine levels were significantly increased following the high-, but not low-, nicotine cigarette. Cortisol levels decreased significantly following the low-nicotine cigarette, and were significantly lower than following the high-nicotine cigarette. DHEA levels were significantly reduced following the low-nicotine cigarette, and significantly increased following the high-nicotine cigarette. Both cigarette types were associated with increased heart rate, with the high-nicotine cigarette producing a significantly higher elevation than the low-nicotine cigarette. The high-yield cigarette was also associated with increased blood pressure. Given that nicotine produced dose-related effects on HPA hormones, the authors conclude that activation of the HPA axis may contribute to the abuse-related effects of cigarette smoking. Mendelson, J.H., Sholar, M.B., Goletiani, N., Siegel, A.J. and Mello, N.K. Effects of Low- and High-nicotine Cigarette Smoking on Mood States and the HPA Axis in Men. Neuropsychopharmacology, 30, pp. 1751-1763, 2005.

This study examined the factor structure and psychometric characteristics of the SCQ-A in smokers with psychiatric conditions, including mood disorders, PTSD, and non-PTSD anxiety disorders, and psychotic disorders. A confirmatory factor analysis of the instrument indicated that the factor structure derived by the instrument's authors provided an adequate fit to the data. In addition, many of the 10 subscales of the SCQ-A demonstrated adequate internal consistency as assessed by Cronbach's alpha as well as adequate test-retest reliability over the course of 1 week. Based on the data derived from this sample, the SCQ-A has adequate psychometric properties for applications involving smokers with psychiatric conditions. Buckley, T.C., Kamholtz, B.W., Mozley, S.L., Gulliver, S.B., Holohan, D.R., Helstrom, A.W., Walsh, K., Morissette, S.B. and Kassel, J.D. A Psychometric Evaluation of the Smoking Consequences Questionnaire-Adult in Smokers with Psychiatric Conditions. Nicotine and Tobacco Research, 7, pp. 739-745, 2005.

Smoking Urge Affects Time Perception

Smokers were divided into high-urge and low-urge conditions, and were informed they would be allowed to smoke in 2.5 min. Measures of time perception were completed, with high-urge smokers reporting 45 s to pass significantly more slowly than did low-urge smokers. The high-urge smokers from the first experiment anticipated (but did not actually report) that their urges would climb steadily over the next 45 min if they were not permitted to smoke. Another group of high-urge smokers reported their urges over 45 min. These urge ratings did not show the steady rise anticipated by the first group. Results suggest that smoking urge may affect time perception and that craving smokers over-predict the duration and intensity of their own future smoking urges if they abstain. Sayette, M.A., Loewenstein, G., Kirchner, T.R. and Travis, T. Effects of Smoking Urge on Temporal Cognition. Psych Addictive Behavior, 19, pp. 88-93, 2005.

Nicotine Increases Impulsive Choice and May Decrease the Value of Delayed Reinforcers

Dr. Jesse Dallery and colleagues have been investigating the effects of acute and chronic nicotine (vehicle, 0.03, 0.1, 0.3 and 1.0 mg/kg nicotine) on impulsive choice behavior in the rat. In these studies, animals made choices between a one- and a three-pellet reinforcer in a discrete trials procedure, with an increasing delay in receiving the larger reinforcer until the pattern of choices reflected indifference between the two alternatives. The latency to make the first response of the session increased under the acute 1.0 mg/kg dose, with no consistent differences in the effects of acute and chronic nicotine on response latency and lever pressing during the delays between choices. Acute injections of nicotine dose-dependently increased impulsive responding. After chronic injections, impulsive responding was increased equivalently regardless of dose, and it was increased even in the absence of nicotine. After drug injections were terminated, behavior remained impulsive for about 30 drug-free sessions, and then responding gradually returned to baseline levels. The results suggest that increases in impulsive choice were not due to anorectic effects, response biases or changes in conditioned reinforcement. Thus, nicotine appears to decrease the value of delayed reinforcers. Furthermore, although chronic nicotine exposure produced effects on impulsive choice behavior that were long-lasting, these effects reversed with the passage of time. Dallery, J. and Locey, M.L. Effects of Acute and Chronic Nicotine on Impulsive Choice in Rats. Behavioral Pharmacology, 16, pp.15-23, 2005.

Agonist Pharmacotherapy For Cocaine

N-[1-(2-benzo[b]thiophenyl)cyclohexyl]pi-peridine (BTCP), a potent dopamine reuptake inhibitor, substitutes for the reinforcing effects of cocaine and meets other criteria for possible agonist pharmacotherapeutic potential. Following the methadone model of agonist pharmacotherapy for opiate addiction, potential agonist pharmacotherapeutic agents for cocaine addiction should substitute for the subjective effects of cocaine, but with a slow onset and sustained duration of action. At the same time, such agents should lack priming effects that may induce craving and lead to relapse. A further desirable feature of such an agent would be the ability to prevent craving elicited by cocaine-related stimuli. The purpose of this study was to determine (1) whether BTCP modifies reinstatement of cocaine-seeking elicited by cocaine-related environmental stimuli and (2) whether BTCP itself produces priming effects. Male Wistar rats were trained to associate discriminative stimuli (DS) with cocaine availability (0.25 mg/infusion) versus non-reward and then were subjected to repeated extinction sessions during which cocaine and DS were withheld. Subsequent presentation of the cocaine associated DS produced recovery of cocaine-seeking (i.e., conditioned reinstatement). Most importantly, BTCP (2.5-30 mg/kg; i.p.) did not attenuate the conditioned reinstatement induced by the cocaine DS. Instead, BTCP potentiated this effect at 10 mg/kg. To test whether BTCP, by itself, exerts priming effects, different groups of rats were trained to self-administer cocaine (0.25 mg/infusion) for 2 weeks. After a 2-week extinction period, BTCP (5, 10 and 20 mg/kg, i.p.) was administered during a test session. Compared to vehicle injections, BTCP reinstated cocaine-seeking at all doses, showing that BTCP not only increases cocaine-seeking induced by cocaine-related stimuli but itself produces priming effects following abstinence. The results suggest that, in cocaine abstinent rats, BTCP produces cocaine-like effects. Its value as a pharmacotherapy, in the manner of methadone, is thereby questionable. Martin-Fardon, R., Lorentz, C.U., Stuempfig, N.D. and Weiss, F. Priming with BTCP, a Dopamine Reuptake Blocker, Reinstates Cocaine-seeking and Enhances Cocaine Cue-induced Reinstatement. Pharmacology, Biochemistry and Behavior, 82, pp. 46-54, 2005.

Brief Access To Sweets Protects Against Cocaine Relapse

Previous research has shown that drugs of abuse can lead to a devaluation of natural rewards, associated with decreases in the intake of sweets or food and, conversely, that the availability of natural rewards (e.g., food) can attenuate cocaine self-administration in animals and humans. The present study used rats to investigate whether brief access to a sweet, palatable solution would reduce both cocaine-seeking and drug-induced relapse following a 3-month period of withdrawal. In this experiment rats were taught to lick a tube to self-administer IV cocaine. After two weeks of training, rats were required to make 20 licks (FR20) on the tube for a single infusion (0.33 mg/0.2 ml of cocaine). Sixteen rats acquired stable cocaine self-administration. These rats were then returned to their home cages for a 3-month period of withdrawal. During the subsequent ten day extinction phase of the experiment, matched groups of 8 rats were given 5 min access to either distilled water or to a palatable solution of glucose and saccharin immediately prior to being placed in the test chambers for a 1 hr extinction session. During extinction, responses to the tube did not lead to cocaine infusions. The results indicated that the rats given 5 min access to the sweetened solution licked significantly less during the first four extinction sessions than those given access to distilled water. Thus, a mere 5 min access to a glucose-saccharin solution reduced cocaine seeking during extinction compared to water controls. Next, a reinstatement procedure was used to test for the effects of the palatable solution on relapse. Following extinction, therefore, both groups of rats were tested for tube licking following IP injections of saline and cocaine (5mg/kg) on separate days. Results showed that while cocaine-induced reinstatement was robust in the water group, it was fully prevented by prior access to the palatable solution. These results represent a first step in providing a scientific foundation for developing therapeutic interventions for cocaine seeking and relapse based on alternative rewards. Liu, C. and Grigson, P.S. Brief Access to Sweets Protect Against Relapse to Cocaine-seeking. Brain Research, 1049, pp. 128-131, 2005.

Extended Access To Cocaine May Not Increase the Motivation To Seek Drugs

Extended access to cocaine self-administration leads to increased drug intake and thus may mimic features of uncontrollable, escalated intake in human addiction. Escalated intake produces shifts in the dose response curve for cocaine self-administration, suggesting that sensitivity to reinforcing effects of the drug is enhanced following high intakes. In another behavioral paradigm, extended access in "binges" produces a dysregulated pattern of intake that may represent disrupted behavioral homeostasis. This disruption can be attenuated by manipulating periods of withdrawal and with non-contingent drug administration or stress. Dr. Dave Roberts and his colleagues recently tested animals that had self-administered cocaine on an extended access schedule, in a progressive ratio (PR) operant schedule for cocaine reinforcement. Break-points from these PR schedules, that is, the maximum number of operant responses an animal makes to receive cocaine, are believed to quantify the strength of motivation for drugs. They also tested the effect of varied periods of drug withdrawal on break points for cocaine. Two studies were conducted with rats trained to self-administer 1.5 or 0.75 mg/kg i.v. cocaine (per infusion) over 40 or 20 days under a fixed ratio schedule. Animals trained with the 1.5 dose were tested in a PR schedule after training and then underwent an escalation regimen with this dose for 6 hours per day over 14 days. Rats in the second study were not assessed in the PR schedule after training, but underwent the same escalation fixed ratio schedule for 14 days with 0.75 mg/kg cocaine. Following the escalation procedure in both studies, animals were withdrawn from drug for either one, or seven days. After this forced deprivation rats were tested for break points. Results revealed that even though all animals increased their cocaine intake during the escalation phase, break points for cocaine did not change after either one or seven days of withdrawal. Thus, there was a dissociation between the increased intake of drug and willingness to "work" to obtain it. While the latter is believed to reflect strength of the drug as a reinforcer, the 6 hour escalation paradigm may mimic increased drug consumption seen during addiction, but possibly not an increased motivation to obtain drug. Furthermore, differences between break point shifts assessed in this 6 hour escalation paradigm, and in a binge model of self-administration, indicates that the patterning of drug intake may be important in changes produced in motivation for the drug. Liu, Y., Roberts, D.C.S. and Morgan, D. Effects of Extended-access Self-administration and Deprivation on Breakpoints Maintained by Cocaine in Rats. Psychopharmacology, 179, pp. 644-651, 2005.

Chronic cocaine has been associated with cognitive deficits on tasks of executive function that are mediated by the frontal cortex. Animal models have been used to study these deficits and relate the functional impairments to specific cortical regions, and other areas known to be important in working memory circuitry. Dr. Kathleen Kantak has been studying cocaine's effects on tasks mediated by different areas of prefrontal cortex such as the prelimbic subregion, the insular/orbital subregion, and associated regions in hippocampus, dorsal striatum and amygdala. Wistar rats in these studies were taught to self-administer a total of 14-18 mg/kg i.v. cocaine (or saline) over two hours per day, Monday through Friday, for 2 _ months prior to behavioral testing in a radial arm maze. Animals were grouped into triads and tested in the maze over 4 more months of 5 days/week cocaine self-administration. Each triad included one animal that actively self-administered cocaine, and two animals that received passive infusions yoked to the schedule of the self-administering rat -- one getting yoked cocaine, and the other, yoked saline. Behavioral tests were conducted in the following manner: Within 30 min after completion of self-administration, catheters were flushed and all rats were tested individually on three tasks: (1) A visuospatially guided delayed win-shift task that requires a functionally intact prelimbic prefrontal cortex; (2) An odor-guided delayed win-shift task that assesses more lateral aspects of the rodent prefrontal cortex and requires a functionally intact insular/orbital prefrontal region; and (3) A win-shift task, which lacks a delay and requires a functionally intact hippocampus. Results from the self-administration data suggest that cocaine was functioning as a reinforcer in animals responding to receive contingent drug infusions. Results from maze testing revealed no differences for contingency (active or passive infusion) or infusion solution (cocaine or saline) conditions on the visually-guided delayed win-shift task. On the (hippocampally mediated) win-shift task, both groups receiving cocaine - those self-administering and those that were yoked - had shorter session latencies at criterion, but speed or latency to acquire the task was not affected. However, on the odor-guided task, only cocaine animals contingently administering cocaine were impaired. These animals required more sessions to reach criterion on the task and made significantly more errors. These differences reveal that long-term daily exposure to cocaine produces a particular pattern of deficits across multiple memory systems. Similar patterns of cognitive impairment have been observed in human cocaine abusers, who perform poorly on tasks that depend upon the orbitofrontal cortex. Moreover, the new finding from the present study is that contingent exposure impairs the ability to learn a task that depends on prelimbic regions of the frontal cortex. Kantak, K.M., Udo, T., Ugalde, F., Luzzo, C., Di Pietro, N. and Eichenbaum, H.B. Influence of Cocaine Self-administration on Learning Related to Prefrontal Cortex or Hippocampus Functioning in Rats. Psychopharmacology, 181, pp. 227-236, 2005.

Marijuana Produces Changes In Sensitivity To Both Reinforcement and the Risk of Loss

Regular marijuana users score higher than non-users on measures of risky behaviors, include high-risk sexual behaviors. However, it is unknown whether risk taking precedes, or is induced, by marijuana use. Laboratory based investigations can assess risk when volunteers are given a choice between two or more options and one of the options has some probability greater than zero of producing either a reinforcing or an aversive consequences, and the probability of the aversive consequence is unknown at the time the risky option is chosen. This procedure has been used by Dr. Scott Lane and his colleagues to assess marijuana associated risk behavior in volunteers who report occasional use of this drug (i.e., two to 12 times per month). The subjects of this study had an average of 7.4 uses in the previous 30 days. All participated in four experimental sessions during which they smoked NIDA supplied marijuana cigarettes and placebo cigarettes. Smoked marijuana doses were either one half of a 1.77% (w/w) delta-9-THC cigarette (plus _ placebo), both halves of a 1.77% cigarette, or both halves of a 3.89% cigarette and were administered by the subjects in a paced, cued smoking procedure. Subjects were trained in the computerized risk-taking task, which was a discrete-trial, two-choice procedure. An algorithm produced a constant probability of monetary reinforcement on any given response and selection of any given option required completion of a variable ratio 25 operant schedule to assess drug effects on motor function after which time the outcome was displayed (i.e., earnings or loss). Cardiovascular and subjective, self-report measures verified the well-known physiological and psychological effects of smoked marijuana. Marijuana did not alter response rates and there was no effect of placebo administration. Risky decisions were evaluated by comparing results on the computerized task prior to, and after, smoking each dose of marijuana. Results revealed that there was a significant difference in risk taking between placebo and the highest marijuana dose. Using first-order Markov transition probabilities, it was apparent that following the 3.89% dose of THC, subjects were more likely to persist on the risky option, whether they were winning or losing. Multiple regression analyses suggested that subjects with stronger and deeper inhalation topographies (i.e., greater CO boost, heart rate change, and number of inhalations) had the greatest increase of risk taking with this high dose. The authors suggest that this dose may affect cortical modulation of behavioral inhibition, and that this is the mechanism responsible for increased risk taking responses, but further investigations will be required to determine the biobehavioral substrates for this drug effect. Lane, S.D., Cherek, D. R., Tcheremissine, O.V., Lieving, L.M. and Pietras, C. J. Acute Marijuana Effects on Human Risk Taking. Neuropsychopharmacology, 30, pp. 800-809, 2005.

A Role For mGlu5 Receptors In Drug Reinforcement and Incentive Motivation

Metabatropic glutamate (Glu) receptors have been implicated in the rewarding properties of drugs of abuse such as psychostimulants and nicotine. For example, mice lacking the mGlu5 receptor do not self administer cocaine, and animals treated with a specific antagonist for this site show reduced intake of both cocaine and nicotine while operant responding for food is unaffected. While these findings provide evidence that central metabatropic Glu receptors are important for the reinforcing properties of these drugs, i.v. self-administration paradigms do not allow for examining motivation to consume the drug. Recently, NIDA supported investigators in the laboratory of Dr. Athina Markou have assessed the effects of the mGlu5 antagonist, MPEP, in rats responding to receive nicotine or cocaine under progressive ratio (PR) schedules of reinforcement. Rats were initially trained on fixed ratio schedules until stable self-administration rates were obtained over three weeks, and then switched to a PR schedule that required increasingly greater responses to receive drug infusions. After four days where stable break points were obtained (the response number where animals stop responding for drug), a single day of extinction testing was conducted during which time stimuli previously paired with operant responding for reward were present, but responses were not reinforced by drug infusions or food. Then, PR responding was re-established and animals were tested with 0 thru 9mg/kg MPEP pretreatment, in counterbalanced order. Results show that, as expected, break points decreased on the extinction test day. Break points for the drugs and for food were also significantly decreased by the mGlu5 antagonist, although comparisons at the highest MPEP dose reveal that break points were more disrupted for drug self-administration than for the non-drug reinforcer. These decreases resemble those seen when animals were tested under extinction conditions without food or drug reinforcement. This outcome suggests that MPEP may be affecting both the motivation to consume drugs of abuse and food. In addition, when break points obtained under extinction conditions were compared to those after the highest dose of MPEP, results suggest that blockade of Glu5 receptors also decreased the motivational properties of secondary reinforcers. While prior studies examining MPEP effects on drug self-administration with fixed ratio schedules suggest that this drug may have pharmacotherapeutic potential for blocking drug reinforcement, the present observations suggest that the Glu5 site may be involved in more general processes of motivation to seek rewards, including behaviors under the control of learned, incentive motivational stimuli. Paterson N.E. and Markou A. The Metabotropic Glutamate Receptor 5 Antagonist MPEP Decreased Break Points for Nicotine, Cocaine and Food in Rats. Psychopharmacology, 179, pp. 255-261, 2005.